Method and composition for enhanced parenteral nutrition

ABSTRACT

A composition and method for improved parenteral administration of nutrients is provided. The method comprises co-administration of nutrients, especially carbohydrates, and an insulinotropic peptide, or its derivatives, analogs, and fragments. The method and composition provide high carbohydrate nutrition while avoiding hyper- and hypoglycemia and their attendant deleterious effects.

BACKGROUND OF THE INVENTION

Patients suffering from a variety of illnesses often need to takenutrition by a route other than through the alimentary canal. Patientsrequiring surgery, patients in comas, patients with digestive tractillness, patients in shock, and patients undergoing healing processesoften receive parenteral administration of carbohydrates along withvarious combinations of lipids, electrolytes, minerals, vitamins andamino acids. Typically this administration is accomplished byintravenous injection or infusion although subcutaneous, intramuscular,peritoneal or other routes may also be used.

When health care professionals administer parenteral nutrients topatients, they take care to avoid blood sugar overload (hypoglycemia).In many cases, even those involving patients with healthy metabolisms,parenteral nutrition can be accomplished and blood sugar levelsappropriately maintained through co-administration of insulin. Thisadministration sometimes, however, has serious drawbacks, since insulinhas a short half-life and can cause significant variation in the bloodsugar levels. Consequently, in serious cases where patients are toreceive a high amount of glucose loading, their blood glucose levels areusually titrated and they receive corresponding infusions of insulin tobalance the blood glucose level. This titration procedure is both tineconsuming and requires a significant expense since the insulin infusionpreferably is continuous and has to be controlled by serial blood sugarmeasurement.

It is well-established that patients suffering from malnourishmentbenefit greatly from rapid delivery of high amounts of nutrients.Usually, oral routes are used for such nutrition so that the health andfunction of patients' digestive processes are maintained. When anon-oral route for nutrition must be used, the risk of hyperglycemia andthe attendant deleterious effects upon osmolarity, kidney tissue,retinal tissue, blood vessels, and the cardiovascular system are greateven if insulin co-administration is practiced. Consequently, thetraditional nutrition therapies, which often do not use insulin, callfor very low rates of nutrient parenteral administration. When a typicalpatient receives such parenteral nutrition, the rate of administrationis maintained at a low value so that the blood sugar (glucose) leveldoes not exceed the normal physiological range of approximately 60 to150 mg per dl. These low rates of administration provide an appropriatesafety factor to avoid hyperglycemia. Usually, the rates range from 50to 150 ml per hour of a 5 to 40 wt/wt. % glucose solution.

Nevertheless, nutrition is a fundamental requirement to enable patienthealing and sustenance. If patients cannot receive adequate nutrition,as many times occurs with traditional parenteral nutrition, healingtakes longer and ancillary problems associated with the patient'sprimary malcondition often occur. Therefore, there often is a need todeliver parenteral trition to a patient at as high a rate as possiblewhile avoiding the deleterious effect of hyperglycemia and avoiding theneed for repetitive or continuous insulin administration and titration.

SUMMARY OF THE INVENTION

These and other objects are achieved by the invention which is directedto a composition and method for maximal parenteral nutritionsubstantially without acute or chronic hyperglycemia. The use of thecomposition in the method of the invention enables delivery of requisitenutrients to satisfy the caloric demand of a patient's healing tissueswhile at the same time maintaining an appropriate blood glucose level.

The composition of the invention includes a source of nutrients and aninsulinotropic peptide. The source of nutrients directly or indirectlyprovides carbohydrate after administered. Preferably the source ofnutrients includes hexoses, pentoses, alcohols thereof and the like,especially those that are highly soluble in aqueous media. Examplesinclude glucose, fructose, galactose, sorbitol, mannitol, zylitol or anycombination thereof. Optionally included can be amino acids,electrolytes, lipids, free fatty acids, monoglycerides, diglycerides,triglycerides, glycerol, salts and minerals. The insulinotropic peptideincludes gastric inhibitory peptide and its derivatives, glucagon-likepeptides such as GLP-1 (1-37) and GLP-1 (7-36), and their derivativeshaving insulinotropic activity including functional group modificationssuch as GLP-1 (1-37) amide, GLP-1 (7-36) amide and GLP-1 (7-36) methylester, their peptide sequence fragments such as GLP-1 (7-34), GLP-1(7-37), GLP-1 (7-36), GLP-1 (7-35), their peptide sequence substitutessuch as GLP-1 (7-34) Ala Phe Ala, their peptide sequence deletions suchas des (Lys) GLP-1 (7-37) amide, their peptide sequence analogsincluding those with non-natural amino acid residues, as well as theirsmall organic molecule mimics. The insulinotropic peptide may be a puresingle compound, a semi-pure single compound or any mixture of compoundssuch a mixture of GLP-1 and GIP. The source of nutrients andinsulinotropic peptide can be combined in a single aqueous medium or canbe contained in separate aqueous media, preferably as a kit.Alternatively, the insulinotropic peptide can be separately formulatedin tablet or sustained release matrix form for delivery by a buccal,subcutaneous or other absorption route. The concentrations of nutrientsand insulinotropic peptides in the composition are described below.

The method of the invention is accomplished by parenteral mixtures ofpeptides administration of the source of nutrients and theinsulinotropic peptide. The administration can be accomplished by priorcombination of the nutrient source and peptide, by theirco-administration from separate sources, by their separate butconcomitant administration or by their separate and sequentialadministration with the insulinotropic peptide being administered first.Individual peptide compounds as well as mixtures of peptide compounds asdescribed above can be administered as the insulinotropic peptide. Theroute of administration for the nutrients can be any parenteral routesuch as intraperitoneal or intravenous while the route for theinsulinotropic peptide can the same as or different from the route forthe nutrients. The concentration of the insulinotropic peptide used maybe any that will deliver and/or maintain normal blood glucose levels inpatients who are receiving the source of nutrients according to theinvention. The concentrations of nutrients in the nutrient source are atleast the same as that typically used for parenteral feeding and therate of administration is at least the same but is preferably higherthan typically prescribed such as preferably a rate providing up to 1000g of glucose or its equivalent per patient per day. The appropriatedosage of insulinotropic peptide is determined by its sigmoidaldose-response curve relative to the blood glucose level. Consequently,the administration of insulinotropic peptide follows athreshold/increasing level/plateau regimen and is balanced with the rateof administration of the nutrient source so that a normal glucose bloodlevel is achieved or maintained while delivering the nutrient source atan administration rate that would cause the blood glucose level toexceed its normal range if the insulinotropic peptide were not alsopresent. Preferably, the carbohydrate concentration in the nutrientsource is in the range of 2% to 50% glucose or its equivalent by weightrelative to the total weight of the source. Preferably, the rate ofadministration of insulinotropic peptide will be calculated to provideand/or maintain at least intermittent peptide blood levels of from 0.1pmol to 0.1 mmol per liter of plasma.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a composition and a method for ofparenteral nutrition of a patient, especially carbohydrate nutrition,without causing deleterious fluctuations in the patient's blood glucoselevel. Substantially more rapid delivery of nutrients is achieved by theinvention relative to traditional parenteral nutrition so that thecalorie demand of the patient's healing cells is almost always met andblood sugar level of the patient does not substantially vary. Theseunexpected and important medical effects are achieved through the use ofa composition of insulinotropic peptides and nutrients such ascarbohydrates, amino acids, lipids, monoglycerides, diglycerides,triglycerides, fatty acids, salts, electrolytes and/or minerals.

Although insulinotropic peptides such as GLP-1, GIP and at least some oftheir fragments, analogs, derivatives and other similar compounds havebeen known for some time, their use has been directed solely to patientswith diabetes. Their application and effect in non-diabetic persons hasnot been suggested. Indeed, the suggested use of insulinotropic peptidesfor treatment of diabetic patients indicates that the insulinotropicpeptides would have an insulin stimulating effect at these patients'ordinary glucose blood levels. Based upon this suggestion, it would seemthat the difficulties occurring with the nutritional administration ofinsulin would also occur with nutritional use of insulinotropic peptide.Such use would require blood glucose level titration and continuousmonitoring of the peptide delivery.

According to the invention, it has been surprisingly found thatexogenous administered insulinotropic peptides do not substantiallyheighten insulin release in a normal patient when he has a normal(non-diabetic) blood glucose level. Furthermore, it has been foundaccording to the invention that when glucose is administered to a normal(non-diabetic) patient by a non-alientary route, the normal regulatorypathway and mechanism for endogenous insulinotropic peptide production,release, receptor interaction and/or past receptor events either do notoccur or are shunted. It has been found that when such a non-diabeticpatient undergoes a change in his blood glucose level so as to exceedhis normal value, such as by non-alimentary administration of glucose,an insulin stimulatory effect caused by exogenously administeredinsulinotropic peptide occurs so as to lower the blood glucose level toa normal value. According to the invention, these discoveries haveresulted in a method of high and rapid nutrition that avoidshyperglycemia while also avoiding the dangers of hypoglycemia owing totoo much insulin and too little blood glucose.

The iisulinotropic peptides are used in combination with the nutritionalmedia to provide parenteral nutrition according to the invention.Stabilization of blood glucose levels is achieved readily andsignificantly with the exogenous parenteral delivery of theinsulinotropic peptides. Especially, insulin secretion during parenteraladministration of nutrients is highly regulated in this fashion so thatincreases in blood glucose are significantly less than would be seenwithout the presence of the insulinotropic peptide. Because anon-diabetic patient has been found to be refractory to theinsulinotropic peptide until the glucose level exceeds the patient'snormal fasting blood glucose level, and because it has been found thatblood insulin levels continue to rise with increasing blood glucoselevels and blood insulinotropic peptide levels up to a plateau, andbecause the blood insulin levels continue to rise with increasing bloodglucose levels even though blood insulinotropic peptide levels are heldat the plateau level, the amount of insulinotropic peptide to beadministered preferably can be standardized irrespective of the amountof glucose to be delivered. Therefore, relative to a nutritional regimenwithout the insulinotropic peptides, more glucose or its equivalent canbe delivered over a shorter time to a patient and the patient's caloriedeficit can be more rapidly and satisfactorily fulfilled by practice ofthe invention. These results are obtained according to the inventionwithout any corresponding side effects from hyper- or hypoglycemia.

According to the invention, the composition to be administered caninclude carbohydrates alone, such as, hexoses or pentoses, specificexamples of which are glucose (dextrose), fructose, galactose, xylitol,mannitol and sorbitol and the like. Alternatively, the composition caninclude an indirect source of glucose such as lipids, fatty acids,diglycerides, monoglycerides, glycerol and/or amino acids which would beconverted to glucose through gluconeogenesis. Electrolytes and mineralssuch as sodium chloride, potassium chloride, magnesium sulfate,potassium gluconate, sodium acetate, potassium biphosphate, potassiumacetate, multiple vitamins and trace elements such as chromium may alsobe present. Preferably, the composition includes a soluble carbohydratesource such as glucose or one which can be readily converted by the bodyto glucose. Preferably, other components included in the composition ofthe invention include a carrier substance such as human serum albumin aswell as electrolytes such as sodium chloride, potassium chloride,magnesium chloride, buffers, stabilizers, and preservatives.

The composition can be delivered by injection or infusion as well as byintramuscular, subcutaneous, intravenous, intrarticular,intraperitoneal, buccal (peptides only), nasal membrane (peptides only)and other non-alimentary routes. The nutrients and insulinotropicpeptides can be delivered by the same or different routes. It isespecially advantageous to deliver the composition by an intravenousroute or to deliver the nutrients by an intravenous route and theinsulinotropic peptides by a buccal route.

The concentrations of nutrients present in the composition and theirrate of delivery are designed to deliver more calories over a 24-hourperiod than possible with glucose solutions alone. The typical, standarddextrose or glucose solution for use in well-known i.v. feeding is a5-40 wt/wt % aqueous glucose solution containing some electrolytes. Thisstandard solution is usually delivered at a rate of 50-100 ml per hourso as to maintain a normal blood glucose level of between 100 and 150milligrams per deciliter. Although this same blood glucose level ismaintained through the method of invention, it is now possible to usemore concentrated solutions of nutrients and deliver them at fasterrates. In particular, the composition of the invention may contain asmuch as about 50% by weight glucose or its equivalent. The rate ofdelivery may also be increased so that a 2%, 5%, 10%, 15%, 25%, 40% or50% by weight solution of glucose or its equivalent can be delivered toprovide up to 1000 gm. of glucose or glucose equivalent per patient perday. Care needs to be taken, of course, so that tissue shock at the siteof injection does not occur from the delivery of the highly concentratedsolutions.

The blood glucose level is maintained at the normal values according tothe invention through the co-administration of the insulinotropicpeptides. These peptides may be administered as individual pure orsemi-pure compounds or in mixture with each other. Consequently, whenthe singular and plural terms “insulinotropic peptide or insulinotropicpeptides” are used in this application, they are meant to cover alldegrees of purity of the peptide as well as the individual forms of thepeptides and their mixtures in any combination. Typically, the peptideis delivered so as to provide blood concentrations on the order ofpicomoles to micromoles per L quantities. The insulinotropic peptidesmay be combined with the nutrients immediately before administration,may be co-administered with the nutrients by use of a separate vesselfor the peptides which leads into a common administration line orseparate lines to the patient, or may be combined with the nutrientsupon manufacture and stored under appropriate conditions to preservepeptide integrity. Alternatively, the insulinotropic peptides can beformulated into pharmaceutically acceptable absorption tabs or tablets,or sustained release matrices such as in a polylactide-glycolide matrix.These solid forms are designed for short to medium term release andabsorption of peptides and are known in the art such as, WO/96/07398, DE3822459, and “Drug Development and Industrial Pharmacy”, 21(17),2013-2019 (1995), the disclosures of which are incorporated herein byreference.

The particular regimen and amount of insulinotropic peptide or peptidesadministered to an individual patient will depend upon the judgment ofthe attending physician and the patient's particular condition. As aguideline, if glucose or its nutritional equivalent is to be deliveredat higher rates so as to provide up to about 1000 g of glucose per dayto the patient, a corresponding larger amount of one or moreinsulinotropic peptides would be delivered up to a plateau level ofabout 3 pmol per kg patient weight per minute. This sigmoidaldose-response curve for the insulinotropic peptide has a threshold levelfollowed by the increasing dosage curve up to a plateau of the foregoinglevel. The dose-response curve is dependent upon the amount of glucosebeing administered and upon the blood glucose level of the patient. Thepatient will be refractory to the insulinotropic peptide effect when hisblood glucose level is within his normal range. The sigmoidaldose-response occurs when the blood glucose level exceeds that normalrange for the non-diabetic patient. At and above that plateau level,insulin stimulation continues and results in increased insulin levels inthe blood but the increase follows the level of blood glucose and notthe insulinotropic peptide level.

Preferably, the insulinotropic peptides are maintained in a separate,sterile, solid state until shortly before their use. To be used, thesolid insulinotropic peptides are preferably combined with sterilebuffered aqueous medium to form concentrations of the insulinotropicpeptide in the range of nmol to mmol per L levels. Alternatively, thepeptides may be combined with a sustained release matrix such aspolylactides, polyglycolides, polycaprolactones, hydrogels, microporouspolyurethanes, polyvinylidene acetate and the like which are known toprovide sustained release of peptides. These formulations can bemanipulated to provide short or medium term release of the peptides. Seefor example U.S. Pat. Nos. 5,364,838, 5,383,848, WO/96/07398, DE3822459, U.S. Pat. No. 5,487,898, “Drug Development and IndustrialPharmacy”, 21 (17), 2013-2019 (1995), “Diabetes Care”, Vol. 19(8),843-848 (1996), “Journal of Medicinal Chemistry”, (Vol. 38, pg.4257-4269) and WO/93/18785, the disclosures of which are incorporatedherein by reference.

The formulas for the insulinotropic peptides used according to theinvention include all known forms of GLP-1 and GIP (the glucagon-likepeptide-1 and the gastric inhibitory peptide) and their derivatives. Inparticular. GLP-1 can be used according to the invention as well as itsderivatives including peptide fragments such as GLP-1 (1-36), GLP-1(1-37), GLP-1 (7-36), GLP-1 (7-37), GLP-1 (7-34), GLP-1 (7-35), similarversions containing substitutions of amino acids such as GLP-1 (7-34)Ala Phe Ala, deletion sequences such as des (Lys) GLP-1 (7-36) amide,analogs with non-natural amino acid residues (e.g., taurine residue,beta and gamma amino acid residues and D-amino acid residues),C-terminal functional group modifications such as amides, esters, andC-terminal ketone modifications and N-terminal functional groupmodifications such as acylated amines, Schiff bases and the like as wellas exendin, glicentin, amylin antagonists and other derivatives such asare described in EP 512042 (Derwent 91-252609/34), WO9325579A1 (Derwent94-OO7457/01), WO9318786 (Derwent 93-3220451/40) WO9011296 (Derwent90-320226/42), U.S. Pat. No. 5,545,618, JP63159323 (Derwent88-224231/32), U.S. Pat. Nos. 5,118,666, 5,120,712, 5,512,549,WO9606628, and EP658568, the disclosures of which are incorporatedherein by reference. Also included are traditional small organicmolecule mimics of the insulinotropic peptides which fit theinsulinotropin receptor sites.

These insulinotropic peptides are known and described in the literature.They can be obtained from natural sources as well as by manufactureusing recombinant technology or automated and classical synthesistechniques. In particular, reference is made to PCT patent applicationNo. 94/08125 which describes the synthesis of GLP-1 (7-36) amide by arecombinant biotechnology technique. The purities of the insulinotropicpeptides may range from semi-pure to highly pure. Their activities inthese various states of purity for example can be obtained throughtitration according to an assay for quantitative insulin release fromisolated B-cells of rat pancreas in a saline glucose solution as istaught by Schmidt in Diabetologia (1985) 28:704-707. The titration willprovide an activity unit quotient which would be used as a basis todetermine the equivalent amount of semi-pure insulinotropic peptide tobe administered relative to the amount of pure insulinotropic peptide.

Stock solutions of the insulinotropic peptide which are useful forpractice of the invention include an isotonic salt solution such as 0.9%sodium chloride containing from 0.1 to 5% (volume/volume) of a carriersubstance such as human serum albumin along with from 1 nmol to 1 mmolper liter of the insulinotropic peptide such as GLP-1 (7-36) amide. Thisstock solution can be diluted by a factor of 20 for use in infusion withthe nutrient solution. Suitable infusion rates for the insulinotropicpeptides will range from 0.01 to 50 pmol of peptide per kg of bodyweight of patient per minute and preferably in the range of 0.2 to 2.5pmol of peptide per kg of body weight of patient per minute. Theadministration rate of glucose co-administered with the insulinotropicpeptide, especially preferably, may range up to 1000 g of glucose perday or its equivalent, and/or from about 10 to about 800 g of an aminoacid mixture per day.

Patients who are especially suited for treatment according to thepresent invention include patients with a disturbed glucose metabolismsuch as insulin resistance but no overt diabetes, as well as patientswho for any reason cannot receive nutrition through the alimentarycanal. Such patients include surgery patients, comatose patients,patients in shock, patients with gastrointestinal disease, patients withdigestive hormone disease, and the like. In particular, obese patients,atherosclerotic patients, vascular disease patients, patients withgestational diabetes, patients with liver disease such as livercirrhosis, patients with acromegaly, patients with glucorticoid excesssuch as cortisol treatment or Cushings disease, patients with activatedcounterregulatory hormones such as would occur after trauma, accidentsand surgery and the like, patients with hypertriglyceridemia andpatients with chronic pancreatitis can be readily and suitably nourishedaccording to the invention without subjecting the patient to hypo- orhyperglycemia. In particular, the administration to such a patient aimsto provide a therapy to as rapidly as possible deliver the nutritionaland caloric requirements to the patient while maintaining his plasmaglucose below the so-called renal threshold of about 160 to 180milligrams per deciliter of glucose in the blood. Although normalpatients not having glucose levels just below the renal threshold canalso be treated according to the invention as described above, patientswith disturbed glucose metabolism such as hyperglycemic patients whoseplasma glucose level is just above the renal threshold also find thetherapy suitable for their condition. In particular, such patients whohave a degree of hyperglycemia below the renal threshold at intermittentintervals can receive a combination treatment of nutrients plusinsulinotropic peptides according to any of the following regimens.Normal patients not suffering from such hyperglycemia can also betreated according to any of the following regiments.

Regimen A

The patient will receive a fixed i.v. dose of the insulinotropic peptidesuch as GLP-1 in an amount between 1 to 2 pmol per kilogram of patientweight per minute. The co-administered i.v. nutrients are titrated tothe patient to reach a steady state plasma glucose level ofapproximately 150 milligrams per deciliter or just below the patient'srenal threshold. The insulinotropic peptide and the nutrient compositionare separately administered through a common i.v. line.

Regimen B

The patient receives a fixed amount of i.v. nutrients according to thepatient's nutritional requirements and the insulinotropic peptide suchas GLP-1 (7-37) is titrated starting at about 0.4 pmol pg per kg patientweight per minute to up to an infusion rate just below a maximum ofapproximately 3 pmol per kg patient weight per minute.

Regimen C

The patient receives a fixed amount of nutrients in a nutritionalcomposition (such as up to 1000 g of glucose per day) in combinationwith a fixed amount of insulinotropic peptide (such as GLP-1 (7-34) atan infusion rate of 2 pmol per kg patient weight per min.). These areadministered through separate or common i.v. infusion lines.

To titrate or otherwise follow the progress of the patient during theinitial stages and periodically during the treatment using thecomposition of the invention, the patient can receive the followingworkups. The patient's blood sugar will be determined at approximatelyevery two hours in the first day and approximately every six hoursthereafter. The patient will have insulin and glucagon blood levelstitrated before and under treatment to optionally determine the bloodinsulin and glucagon levels in the patient. The patient optionally mayreceive indirect calorimetry to determine the patient's glucoseoxidation rate and energy expenditure in order to determine thepatient's nutritional need and whether his caloric level needs to beincreased, decreased or maintained.

The invention has been fully characterized according to the foregoingdescription. The following examples and protocols provide detailedembodiments of some aspects of the invention. The invention however isnot limited to these embodiments and aspects.

Protocol

Provision of Incretin Stimulation of the Insulin Secretion throughExogenous GLP-1 (7-36) Amide During Parenteral Nourishment

The goal of this protocol is to ameliorate the problems associated with:parenteral nourishment. It is very often not possible to infuse adesired amount of glucose even to people with healthy metabolism withoutprovoking hyperglycemia (1). Therefore it is necessary even withnon-diabetics to add insulin. This results in many time- andmoney-consuming control tests and limits glucose uptake.

A possible reason for the insufficient endogenous insulin secretion isthe lack of the incretin stimulation. Incretin stimulates the secretionof insulin through the effect of intestinal hormones released after oralglucose intake. This stimulation is much better than the insulinincrease caused by increasing plasma concentration of such substrates asglucose and amino acids alone. Two of these incretin hormones from theintestines, GLP-1 (7-37) (i.e., the acid) and GLP-1 (7-36) amide, have avery strong glucose-dependent insulinotropic and glucagonostatic effect.High doses of such incretins do not lead to hypoglycemia by healthypeople, because those incretins have been found in animal tests to havehardly any influence on insulin secretion at normal (sober) plasmaglucose values.

Insulin secretion during parenteral nourishment in the presence of GLP-1(7-36 amide) can be controlled such that the plasma glucose increasewill be less than without GLP-1. Therefore more glucose can be deliveredover a 24 hour period than otherwise. The calorie deficit seen withparenterally nourished patients can be better satisfied.

PART A

The study is conducted as follows. Patients include both sexes betweenthe ages 18 and 75 who are dependent on parenteral nourishment. Patientsare excluded if they suffer from acute diseases (i.e., fever), andinsulin-dependent diabetes and restricted liver and kidney functions(kreatinin>1.2 mg/dl), pregnancy, anemia (hemoglobin<10 g/dl) andtreatments with mechanical breathing support and catecholamines. Everypatient participates in one study day.

To begin the study, a constant central venous infusion of glucose/aminoacid mixture (Aminomix, Frescnius AG) without the infusion of atriglyceridr suspension should be used to continue the parenteralnourishment already in progress. The dose corresponds to the clinicallydetermined calorie demand of the patient. The plasma concentrations ofglucose, free fatty acids, triglycerides, amino acids, insulin,C-peptide and GLP-1 (7-36 amide) levels naturally present should bedetermined every hour for the next 4 hours in the “steady state”. If theglucose concentration in this “steady state” is above 150 mg/dl, asterile and pyrogene free solution of GLP-1 (7-36 amide) (1.2pmol/kg/min) should be infused for the next 4 hours and all the abovevalues should be measured again in 1 hour intervals. This dosecorresponds to the normal “substitution dose” for the incretin hormoneGLP-1 (7-36) amide (0.3-0.4 pmol/kg/min) (2) and the necessarypharmacological dose for type 2 diabetics of 1.2 pmol/kg/min (7,8). Thetreatment is expected to stimulate the insulin secretion andsubsequently normalize the plasma glucose. Supplementing this study areindirect calorometry measurements (Deltratrak, Datex, Finland).Therefore 20 min measurement periods are necessary at the start, after 4hours and at the end of the GLP-1 (7-36) amide infusion period of 8hours. It is also possible to determine changes in the substrateutilization (glucose and lipid oxidation, energy consumption) from thesemeasurements.

PART B

Every patient participates in three study days.

To begin the study, a constant central venous infusion of glucose/aminoacid mixture (Aminomix, Fresenius AG) without the infusion of atriglycerid suspension should be used to continue the parenteralnourishment already in progress. Placebo, GLP-1 (7-36) amide (0.6pmol/kg/min) with possible changes up to 1.2 pmol/kg/min according toresults of study A and insulin (2U per hr.) should be infused in arandom day order. Plasma glucose concentrations should be determinedevery half hour for the next 6 hours. The glucose infusion should beincreased to reach a “steady state” glucose concentration of 150 mg/dlvery fast and kept at this level. To supplement this study glucose, freefatty acids, triglycerides, amino acids, insulin, C-peptide and GLP-1(7-36 amide) should be measured every hour. Indirect calorometry ispreformed at the start and end of the 6 hour period.

For taking blood samples it is necessary to place one peripheral veincatheter besides the central vein catheter. Physiological NaCl is slowlyinfused to keep the vein “open”.

GLP-1 (7-36) amide should be received as a GMP product and should bestored at −30° C. as a sterile stock solution (in 0.9% NaCl with 1%human serum albumin). Samples are taken before infusion,sterile-filtered and tested for bacteria growth and endotoxins with thelimulus assay.

Blood samples should be taken at the following time points: 0, 60, 120,180, 240, 300, 360, 420, 480 (study A) and: 0, 60, 120, 180, 240, 300,360, 420, 480, 540, 660 and 720 (study B).

The statistical analysis can be done with repeated measurement analysisof variance supplemented by one-way ANOVA and t-tests.

EXAMPLE

A 60-year old patient was fed parenterally because of inflammatory boweldisease. He weighed 75 kg. The parenteral nourishment was delivered by ainfusomate through a central vein catheter and consisted of 1.5 liter ofa 40% glucose solution to deliver approximately 600 g of glucose in 24hrs and 1 liter of a 10% commercial amino acid mixture. The blood sugarvalues achieved without GLP-1 (7-36) amide were between 160 and 190mg/dl. Then GLP-1 (7-36) amide was administered and the blood glucosevalue was decreased to about 100 mg/dl even though the patient's highrate of glucose administration was continued.

GLP-1 or GIP may be used as a companion medication. The insulinotropicpeptide medicament was prepared by a 20:1 dilution of the followingstock solution of peptide using normal saline. A stock solution ofGLP-1, containing 50 μg/ml and dissolved in 0.9% NaCl with the additionof human serum albumin (end conc. 1% vol/vol) was prepared. The solutionwas tested for bacterial contamination and pyrogenes and can be storedfor 3 months (frozen at −30° C.).

1. A method of enhancing metabolism of nutrients, comprisingadministering by a parenteral route to a non-diabetic patient in need ofenhancing metabolism of nutrients a nutritively effective amount of oneor more nutrients or any combination thereof and one or moreinsulinotropic peptide or peptides, wherein said peptide or peptides isGLP-1, GLP-1 (7-34), GLP-1 (7-35), GLP-1 (7-36), GLP (7-37), thedeletion sequences thereof, the natural and non-natural amino acidresidue substitutes thereof, the C-terminus carboxamides thereof, theC-terminus esters thereof, the C-terminus ketones thereof, theN-terminus modifications thereof, or any mixture thereof.
 2. A method ofenhancing metabolism of nutrients, comprising administering by aparenteral route to a patient with a disturbed glucose metabolism, asurgery patient, a comatose patient, a patient in shock, a patient withgastrointestinal disease, a patient with digestive hormone disease, anobese patient, an atherosclerotic patient, a patient with vasculardisease, a patient with gestational diabetes, a patient with liverdisease, a patient with liver cirrhosis, a patient with glucocorticoidexcess, a patient with Cushings disease, a patient with activatedcounterregulatory hormones that occur after trauma or a disease, apatient with hypertriglyceridemia, or a patient with chronicpancreatitis, a nutritively effective amount of one or more nutrients orany combination thereof and one or more insulinotropic peptides.
 3. Themethod of claim 1, wherein said insulinotropic peptide or peptides isGLP-1(7-36) amide.
 4. A method of enhancing metabolism of nutrients,comprising administering by a parenteral route to a patient in need ofenhancing metabolism of nutrients a nutritively effective amount ofglucose and one or more insulinotropic peptide or peptides, wherein saidinsulinotropic peptide or peptides is GLP-1, GLP-1 (7-34), GLP-1 (7-35),GLP-1 (7-36), GLP (7-37), the deletion sequences thereof, the naturaland non-natural amino acid residue substitutes thereof, the C-terminuscarboxamides thereof, the C-terminus esters thereof, the C-terminusketones thereof, the N-terminus modifications thereof, or any mixturethereof; wherein the administration of the nutrient(s) produces a bloodglucose level in the patient of from about 80 to 180 mg glucose perdeciliter of blood, and the rate of administration is calculated todeliver up to about 1000 g of glucose or its equivalent per patient perday.
 5. The method of claim 1 wherein said nutrient is one or more aminoacids, lipids free fatty acids, mono- or diglycerides or glycerol, orany combination thereof.
 6. A method for non-alimentary nutritioncomprising administering by a parenteral route to a patient in need ofparenteral nutrition, a nutritively effective amount of one or morenutrients selected from the group consisting of carbohydrates, ammoacids, lipids, free fatty acids, mono-or diglycerides, glycerol and anycombination thereof; and one or more insulinotropic peptides, whereinthe insulinotropic peptide is GLP-1, wherein the administration of thenutrient(s) produces a blood glucose level in the patient of from about80 to 180 mg glucose per deciliter of blood, and the rate ofadministration is calculated to deliver up to about 1000 g of glucose orits equivalent per patient per day.
 7. The method of claim 1 wherein theinsulinotropic peptide is an exendin.